The leading cause of cancer-associated deaths is tumor metastasis, the ability of the primary tumor to invade distant sites. Thus, an understanding of the underlying mechanism for tumor metastasis, and the factors that control it, is a major challenge studying oncogenesis. Metastasis is a complex involving both tumor-intrinsic factors (genetic or epigenetic alteration to the tumor cells) and extrinsic factors provied by the tumor microenvironment. These extrinsic factors can include cytokines expressed by tumor-associated stromal cells and infiltrating inflammatory cells, changes in the extracellular matrix surrounding the tumor, and alterations in blood and/or lymphatic vessels within the tumor. These factors combine to create a microenvironment that can both promote tumor growth, through the expression of cytokines and the generation of tumor-specific immune suppression (regulatory T cells and myeloid-derived suppressor cells), and the production of factors, such as proteases, capable of breaking down the matrix and allowing the tumor to escape and metastasize. However, it remains unclear how these various processes are regulated. We have found that the cytokine thymic stromal lymphopoietin (TSLP) is critically involved in the control of metastatic breast cancer. TSLP expression by both the tumor and the host regulates tumor metastasis;and loss of TSLP, either genetically through gene disruption or via neutralization, dramatically reduces tumor growth and inhibits metastasis. TSLP can also induce the development of myeloid-derived suppressor cells, and increase their ability to suppress immune responses. Based on this preliminary data, we propose to: 1. Determine the role of TSLP in tumor growth and metastasis;2. Identify TSLP-regulated factors that are involved in tumor progression;3. Determine the role of TSLP in the development and function of myeloid-derived suppressor cells. These studies will provide important insights into the role of TSLP in metastatic breast cancer, and allow for preclinical evaluation of TSLP blockade as a therapeutic intervention in breast cancer.
Metastatic breast cancer is a devastating disease, with over 230,000 new cases expected in 2013, resulting in nearly 40,000 deaths. A better understanding of the factors that control tumor growth and metastasis may lead to new therapeutic targets. We have found that the epithelial cytokine thymic stromal lymphopoietin (TSLP) is produced by breast tumors, and that blockade of TSLP inhibits tumor growth and prevents metastasis. The studies in this proposal will extend this work to investigate the mechanisms that underlie the role of TSLP in tumor progression.
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